Angiogenesis is central to the pathophysiology of rheumatoid arthritis (RA), and anti-angiogenic therapy targeting vascular integrin alphavbeta3, a crucial effector of the angiogenic process, may provide a novel approach to the treatment of this disease. The Specific Aims of this Mentored Clinical Scientist Development Award are [1] To characterize the dominant integrin pathway promoting angiogenesis in human RA, [2] To evaluate the effects of rational combination therapy targeting angiogenesis, cytokine-induced inflammation, and T cell mediated immunity, to determine the relative contribution of angiogenesis to the pathophysiology of RA, and provide pre-clinical evaluation of potential synergistic therapeutic effects, and [3] To examine the molecular mechanism of alpha V integrin-mediated endothelial cell survival during angiogenesis. The proposed research plan, in addition to providing valuable information, will equip the applicant with the necessary skills and techniques to investigate molecular mechanisms of cell function and signal transduction and perform anti-angiogenic gene delivery strategies as an independent investigator. Antagonists of alphavbeta3 are presently being evaluated in phase I/II cancer trials, and the results of this proposed study will provide the basis for alphavbeta3 antagonist therapy in future human arthritis trials. The strength of this career development award is based on the Mentor, Dr. David Cheresh, an international leader in angiogenesis research with a solid history of fostering the development of independent researchers. In addition, The Scripps Graduate Program in Macromolecular and Cellular Structure and Chemistry, in conjunction with The Scripps Research Institute and the Cheresh Laboratory, provide an outstanding training environment with exposure to state-of-the-art technology, permitting collaboration and intellectual exchange with many leading investigators. This comprehensive career development plan, in addition to the proposed research project will guarantee successful maturation of the applicant from physician to physician-scientist.